A statistical thermodynamic approach for predicting the sequence‐dependent nucleosome positioning along genomes

Abstract

Nucleosomes are the fundamental repeating unit of chromatin and constitute the structural building blocks of the eukaryotic genome. The distribution of nucleosomes along the genome is a significant aspect of chromatin structure and influences gene regulation through modulation of DNA accessibility. For this reason, an increasing interest is arising in models capable of predicting the nucleosome positioning along genomes. Toward this goal, we propose a theoretical model for predicting nucleosome thermodynamic stability in terms of DNA sequence. The model, based on a statistical mechanical approach allows the calculation of the canonical ensemble free energy involved in nucleosome formation. The theoretical free energies were evaluated for about one hundred nucleosome DNA tracts and successfully compared with those obtained in different laboratories with nucleosome competitive reconstitution (correlation coefficient equal to 0.92). We extended these results to the nucleosome positioning along genomes. To test our model, the theoretical nucleosome distribution was compared with that of yeast genome experimentally determined. The results are comparable with those obtained by different authors adopting models based on identifying some recurrent sequence features obtained from the statistical analysis of a very large pool of nucleosomal DNA sequences provided by the positioning maps of genomes.

Nucleosome Positioning in Saccharomyces cerevisiae

“…However, the accuracy of these models depends greatly on the quality of the data about the physical properties of DNA loci and the exact influence that these properties have on nucleosome formation. Several studies reported physical models; however, their genome-wide accuracy has not yet been thoroughly investigated (111,118,152,178,182).…”

Nonspecific Transcription-Factor-DNA Binding Influences Nucleosome Occupancy in Yeast

“…Intrinsic DNA sequence preferences of nucleosomes, has been a long-standing question for more than three decades [22][23][24][25][26][27][28]. Yet, a general answer to this question at the genome-wide level is still debated and a matter of active research [5][6][7]10].…”

A deformation energy-based model for predicting nucleosome dyads and occupancy

“…In recent years, experimental mapping of genome-wide nucleosome organization has been obtained for several model systems 33 34 35 36 37 38 , such as Saccharomyces cerevisiae , Caenorhabditis elegans , Drosophila melanogaster and Homo sapiens , but the mechanism of nucleosome positioning still remains elusive. A variety of models have been proposed for predicting nucleosome occupancy that are classified into categories of bioinformatics 19 39 40 41 42 43 44 45 and energetics of nucleosomal DNA 46 47 48 49 50 51 52 53 54 . Bioinformatics models learn various sequence features, such as dinucleotide distributions and oligonucleotide motif frequency from a large quantity of nucleosomes 39 40 41 42 43 .…”

“…There are a number of energetics models designed to predict nucleosome formation energy, nucleosome occupancy and positions 46 47 48 49 50 51 52 53 54 . A model 51 that took into account the deformations of DNA helical twist, roll and tilt achieved a moderate correlation between its prediction and experimental nucleosome occupancy (R = 0.45, P < 0.0001, on yeast chromosome III).…”